Synthesis of Modified Benzyltetrahydroisoquinoline Alkaloids

Even more than 60 years after the first total synthesis of morphine by Gates [139, 140], the ongoing interest of synthetic chemists in the natural product is evidenced by the numerous approaches to the morphinan skeleton, as well as formal and total syntheses of the natural product. The progress in morphine synthesis has been reviewed on several occasions [141-143]. 

Herein, three syntheses of morphine or related alkaloids are discussed in detail, which utilize completely different protocols for the coupling of the ring motifs of the alkaloid. Rice published a biomimetic approach with an acid-mediated electrophilic cyclization strategy as key step [144]. Mulzer employed a Friedel-Crafts acylation and a Robinson annulation to construct the phenanthrenone ring system [145]. The D ring of the alkaloid was elaborated with a 1,4-cuprate addition as key step. In his most recent contribution to morphine research, Hudlicky employed a Diels-Alder cycloaddition reaction to construct the ABCE ring system of the natural product. The requisite diene was obtained after oxidative dearomatization of the A ring precursor [146]. 

The route commenced with the condensation of amine 229 and carboxylic acid 230 at 200 °C. Subsequent Bischler-Napieralski reaction and sodium borohydride reduction established the C/D ring system of morphine and delivered tetrahydroisoquinoline 231 in good yield. Next, Birch reduction and Af-formylation afforded enol ether 232, which was converted into the corresponding ketal before reaction with bromine allowed the isolation of the cyclization precursor. The halide in 233 serves to protect the para position in the aromatic ring in the subsequent acid-mediated electrophilic cyclization reaction—a common strategy that has also been applied by other research groups in their endeavors toward morphine and related alkaloids. 

As dihydrocodeinone has been converted to morphine before, this hydrogenation concludes the formal synthesis of this important alkaloid. The completion of the synthetic route included the conversion of the tertiary amine into the corresponding carbamate before the C7-C8 unsaturation 

Most other approaches toward the title alkaloid featured Heck reactions [152], Claisen rearrangements [153], or Diels-Alder reactions [139, 154]— Mulzer s route is the only one so far that utilized a 1,4-cuprate addition to install 

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